Good regulators of black boxes

Wrestling with some reporting on Ozempic

Diet is such a complex and mystifying part of well-being. Your doctor always tells you that diet is a means to a long and healthy life. But eating is also essential to being a person and being in a community. We eat when we celebrate and when we mourn. We must eat to live, but we also must eat as part of cultural ritual. Pulling the cultural component of diet out of the biological component is impossible.

And yet, we try, because many of us find ourselves in an unhealthy relationship with food. A friend sent me this article in the Wall Street Journal about the hottest drug on the block, Ozempic. Check out this lede:

Ozempic and similar drugs are transforming the world’s understanding of obesity. It isn’t so much about willpower: It’s about biology.

What a start! What is the difference between willpower and biology? Is the WSJ about to dive into a deep ontological breakdown of the philosophy of mind? Sadly, it doesn’t. The article continues to say that the overabundance of unhealthy snacks is contributing to a spike in obesity. But if that’s the case, isn’t it about capitalism, not biology? The reporter doesn’t seem particularly interested in the complexity of food’s role in our lives, but rather in unpacking what makes this latest diet pill better than all of the ones that have come before.

The party line being fed to the reporter by scientists is that food consumption levels are an adaptive system with a setpoint that is adjusted by experience. If this is true, then diet is another example in my list of n-of-1 protocols. The argument is that your nervous system moves its set point higher and higher with more food consumption, and once it is so high, it doesn’t come down:

The amount is like a setting on a dial, or what many researchers call a “set point” or “defended fat mass.” The brain maintains the dial setting or set point by regulating how much a person eats. Ozempic, its sister drug Wegovy and another, Mounjaro, lower the dial setting, or set point, in effect by acting on the brain to reduce hunger and make a person feel full sooner, some obesity researchers say.

In other words, Mounjaro is saying that the body has a variety of control systems, and the brain (but not the mind) sets the one that regulates eating. The current argument advanced by many doctors, biologists, drug companies, and the Wall Street Journal is pharmaceutical intervention is the only way to change the set point.

The new medicines have put some long-held assumptions about weight and health on the chopping block. “What these drugs have proven is that patients are right: It’s not their fault,” said Dr. Louis Aronne, an obesity treatment specialist and professor of metabolic research at Weill Cornell Medical College. 

He and many other specialists who study obesity or prescribe the new drugs have advised or conducted studies for the companies making them.

Proud of the WSJ for adding the COI at the end there.

I’m bemused by the absolutist arguments in this article. Just as evidence that everyone is confused, the reporter tells us that at least 1,500 genes are linked with weight, but fails to mention we probably only have about 20,000 genes. If 10% of the genes are linked with something, you haven’t found a causal explanation in the genome.

Obviously, obesity is a complex condition. I am being flippant about the assuredness of the quoted experts in this article, but I am not being flippant about how difficult people can find weight management. This is a very real, very pervasive problem that demands investment in solutions.

It’s certainly plausible that this sort of drug works by the described mechanisms. The body regulates many things with hormones. Messing with hormone pathways can change those regulatory loops. The idea that interfering with a hormone can suppress appetite is not far-fetched.

And it’s also believable that the body gets dysregulated when put in conditions it shouldn’t be in. Sepsis is a regulatory disorder triggered by infection. Many cancers are understood to be regulatory diseases triggered by overzealous repair. Obesity may very well be another example, where years of overeating pushes a body into a bad regulatory state that is difficult to recover from.

Unfortunately, we are still in the early days of figuring out how to move someone’s set-point back to normal. When people stop taking drugs like ozempic, their set point seems to swing back to what it was before. The last line of the article concedes.

Researchers want to figure out what makes the set point go way up for some people, leading to obesity, Kaplan said: “For the moment, it’s a black box.”

Ozempic and it’s GLP-1 receptor agonist cousins raise an interesting question. If we have found a drug that can move a set point, why can’t we move this set point ourselves? On the blog here, I’ve discussed a variety of therapies that involve slow changing of biological set points. What makes obesity different? Is it different? We certainly know that some people can change their relationship with food and sustain this change for long periods. But then why are some people able to “use willpower” and others a “victim of biology?” Perhaps the issue is that obesity needs early treatment. It may be that resetting a set point is impossible once a system is too dysregulated. In diseases of dysregulation, whether it be obesity, cancer, or sepsis, when is it possible to steer a person headed toward dysregulation back to normal?